Lactonization, a well-known process is widely used in the preparation of statins. In this process δ-hydroxy carboxylic acid loses one molecule of water to form an intramolecular ester—a lactone. It is an equilibrium reaction as illustrated in the scheme below and therefore, some means of shifting the equilibrium to the “right” is required to achieve the product in high yield and purity.

Several methods are known in the prior art for lactonization of lovastatin or synthesis of simvastatin. All these methods broadly fall into two categories i.e. thermal dehydration or acid catalysed cyclization.
U.S. Pat. No. 4,444,784 to Hoffman et al., U.S. Pat. No. 4,582,915 to Sleteinger, et al., U.S. Pat. No. 4,820,850 to Verhoeven et al., and U.S. Pat. No. 6,307,066 to Keshava et al., describe the lactonization processes, by heating the statin acid and/or ammonium salt in a suitable solvent such as toluene, butyl acetate, ethyl acetate, cyclohexane to boiling, whereby the azeotropic mixture of the solvent and the water is removed by distillation and the reaction equilibrium is shifted to the formation of the lactone. The process of lactonization at reflux temperatures is complicated by the formation of dimeric impurity of Formula [III]. Moreover, its removal from the product is difficult, thereby affecting the quality of the final lactone product. To minimize dimerization, high dilutions are often used in the lactonization reaction, which is disadvantageous on large-scale manufacturing. Another disadvantage of these processes is that long reaction time is required for completing the reaction, thereby reducing the manufacturing capacity.

U.S. Pat. No. 4,916,239 to Treiber, U.S. Pat. No. 5,917,058 to Kumar et al., and U.S. Pat. No. 5,159,104 to Dabora et al., disclose lactonization processes by treating the open ring hydroxy acid form of the statins preferably in their ammonium salt form in the presence of a strong acid catalyst or a mixture of acid catalyst and water. The resulting lactonized product is isolated after completion of the reaction by the addition of anti-solvent selected from water, hexane, heptane or cyclohexane and the like. The strong acid catalyst used in the process varies from 1.2-1.5 molar equivalents, and is difficult to handle and poses industrially unacceptable disposal problems especially on an industrial scale. The reaction and the subsequent work-up takes about 9-12 hours thereby decreasing the efficiency of the process.
Similarly U.S. Pat. No. 6,562,984 to Peters, et al., describes the lactonization of statin acid or its salt in solvent selected from dichloromethane or acetonitrile under anhydrous reaction conditions in presence of organic or inorganic catalyst with the removal of insoluble hydrated complex formed during the lactonization reaction. However, in this method removal of the insoluble hydrated complex from the reaction mixture and thereafter its disposal reduces the efficiency of the process.
In addition, many of the lactonization methods of the prior art require the use of the strong mineral acid or an organic acid catalyst, thereby making the process hazardous and moreover these corrosive reagents require special care to handle. Furthermore, the generation of large amount of effluent requires special treatment procedures. All these require additional investments thereby increasing the cost of production. In addition, some of the prior art methods describe the lactonization reaction at subzero temperature thereby adding the additional utility costs.
Therefore, there is a need to develop an easy to operate, industrial friendly and yet cost effective process for preparing lactone compounds and still this process should ensure the formation of dimeric impurity to a level less than 0.1%. The present invention addresses these needs.